In Alzheimer disease (AD), the appearance of neurofibrillary tangles (NFTs) — comprising aggregates of hyperphosphorylated tau — parallels the development of neuronal loss and cognitive decline, leading to speculation that NFTs might be pathogenic. However, it has also been suggested that tau aggregation might be part of a homeostatic response to neuronal damage. In addition, neuronal subtypes and biochemical pathways seem more susceptible to NFTs in some brain areas than others — but the mechanisms of this are poorly understood. Here, Otero-Garcia et al. developed an approach that combined high-throughput fluorescence-activated cell sorting (FACS) with single-cell RNA sequencing (scRNA-seq) to compare the molecular signatures of NFT-containing and NFT-lacking soma in tissue samples from individuals with and individuals without AD. They found that susceptibility to cell death was broadly similar between NFT-containing and NFT-free neurons, but marked associations were found between the presence of NFTs and indicators of cellular stress and synaptic dysfunction.

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